Antigen-specific help is an essential feature of acquired immunity. The regulated differentiation of type 1 and type 2 cytokine production (IFN- gamma versus IL-4, IL-5-dominated, respectively) and help, in turn, determine susceptibility to microbes, autoimmunity, and allergic inflammation. Although type 1 and type 2 cytokine production appear to be uncoupled in many disease, experimental and genetic manipulations typically have cause reciprocal effects of Th1 and Th2 cells. To investigate the regulation of antigen-specific T cells responses and disease susceptibility, we have created two new transgenic mouse models. As a focus for studying immuno-regulation in a disease-related context, we will employ a mouse model of antigen-inducible airway hyper-responsiveness (AHR). Cytokines characteristic of type 2 T cells (IL-4 and IL-5) are crucial pathogenic components in the inflammation association with allergic airway disease and AHR. Because so many known features of these allergic processes can be produced by Th2-dependent cytokines, asthma has been increasingly viewed as "a Th2 disease." However, other findings indicate that Th2 cells may not fully account for the T cell contribution to allergic inflammation. The overall goal of the proposed research is to dissect additional immunologic mechanisms that contribute to the development of antigen-inducible AHR. A key hypothesis is that activation of T cells in addition to those which provide type 2 help is essential for the full development of AHR. This hypothesis will be tested using transgenes whose expression is targeted to the T lineage. Our transgene encodes a chimeric cytokine receptor, so that IL-2 binding to activated T cells leads to intracellular signaling characteristic of IL-4 as well as IL-2, and type 2 help is selectively enhanced. Experiments in Specific Aims 1 and 2 will investigate immunologic consequences of this immune deviation and determine if it is sufficient to overcome completely the lower responder phenotype of C57BL mice in the OVA-induced AHR model. The other transgene [IkappaBalpha(deltaN)] inhibits signaling through the NF- kappaB/Rel pathway in T cells. Surprisingly, the observed inhibition of OVA-inducible AHR was accompanied by evidence of intact type 2 help despite inhibition of type 1 help. Experiments proposed in Specific Aim 3 will measure Th1 and Th2 development in vivo and investigate the requirement for cells other than type 2 helper cells in AHR. We will use T cell transfer experiments to determine if restoration of type 1 help is sufficient (Stat6-deficient T cells) or necessary (using IRF-1-deficient CD4+ T cells) to restore AHR susceptibility in IkappaBalpha (deltaN) mice, and elucidate the requirement for functional CD8+ cells in this system.